1383

J Physiol 588.9 (2010) p 1383

PERSPECTIVES
Peripheral artery disease: can
enhanced vascular reactivity
jumpstart the effectiveness of
exercise training?
Judy M. Muller-Delp
Department of Physiology and
Functional Genomics, University of
Florida, Gainesville, FL, USA
Email: jdelp@ufl.edu

Peripheral arterial disease is a chronic

disease with significant cardiovascular
risk. Patients with peripheral artery
disease experience pain in leg muscles
during walking which is only relieved by
rest (intermittent claudication) (Stewart
et al. 2002; Prior et al. 2004). The goal
of treatment in patients is to improve
quality of life by minimizing ischaemic
symptoms and preventing progression to
vascular occlusion. Therapeutic strategies,
including exercise-based interventions and
exercise training, have been reported to
increase pain-free walking and quality of
life in these patients (Stewart et al. 2002;
Watson et al. 2008). Meta-analysis has
shown that the greatest improvements
in walking occur when exercise sessions
are of at least 30 min in length and when
these sessions occur a minimum of two
times per week (Gardner & Poehlman,
1995). Thus, the
effectiveness of
exercise as a therapeutic intervention
may
be limited if ischaemic pain
prevents patients from
performing
exercise of sufficient length
and
frequency. Interventions that
jumpstart the benefits of exercise training
by reducing ischaemic pain during initial
training bouts could enhance the overall
effectiveness of exercise therapy. In a
recent issue of The Journal of Physiology,
Colleran et al. (2010) report that exercise
training, in addition to contributing
to remodelling of collateral-dependent
arteries, promotes endothelial function
and vasodilatory responsiveness. If
the mechanism(s) by which exercise
training enhances endothelial function
in collateral-dependent arteries can be

identified, therapeutic interventions could

be designed to reduce ischaemia during
initial bouts of exercise training, thereby
increasing exercise duration and promoting
adherence to training by reducing
ischaemic pain.
Studies involving experimental animal
models of peripheral artery disease have
demonstrated the presence of a collateral
circuit capable of circumventing the
vascular obstruction in the lower limb
(Yang et al. 1996, 2008); the conductance
of this circuit increases following occlusion
of a primary hind limb artery. Exercise
training has been shown to enhance blood
flow through this collateral circuitry in
animal models of occlusive artery disease
(Yang et al. 1996, 2008). Improvements
in collateral-dependent blood flow
to hindlimb muscles that occur with
exercise training in these occlusive
models are accompanied by remodelling
and enlargement of collateral vessels.
Much of the functional improvement that
occurs with exercise training in the
occluded hind- limb has been attributed
to
enlargement of these collateral
vessels, presumably stimulated
by
increases in shear stress during periods
of activity (Prior et al.
2004); however, the ability of exercise to
alter the reactivity of collateral vessels has
remained relatively unexplored. Colleran
et al. (2010) present results from a study
in which vascular reactivity of collateral
vessels from the occluded hindlimb was
assessed following 3 weeks of exercise
training. They report that exercise
enhanced vasodilatory responses to both
acetylcholine and flow in peripheral
collateral arteries. Exercise training has
been reported to enhance endotheliumdependent
vasodilatation of skeletal
muscle arteries and arterioles in the
absence of occlusion (Spier et al.
2004). Colleran et al. (2010) have reported
that exercise training increases endothelial reactivity in collateral-dependent
arteries, even when assessed at a low
intraluminal pressure of 45 cmH2 O,
approximating conditions present distal
to an occlusion. These results suggest
that exercise training provides a stimulus
sufficient to alter endothelial function even

under conditions of reduced intravascular

pressure.
Importantly, the exercise training-induced
improvement in flow-induced vasodilatation of peripheral collateral arteries
persisted even in the presence of blockade
of both nitric oxide synthase and cyclooxygenase pathways, suggesting that an
alternative pathway contributes to the
exercise training-induced enhancement of
endothelial function in collateral arteries.
This differs from reports that implicate
nitric oxide signalling as the primary target
of exercise training in skeletal muscle
arteries and arterioles (Spier et al. 2004).
The results of the study by Colleran et al.
(2010) indicate that for a complete understanding of the role played by collateral
vessels in exercise-induced amelioration of
hindlimb bloodflow, careful examination of
endothelial signalling pathways must occur.
Indeed, if these pathways are carefully
evaluated, the benefits of exercise training
could be augmented by combined therapy
which enhances endothelial function of
collateral-dependent vessels in patients
that experience significant ischaemic pain
during bouts of exercise. Therapeutic
intervention targeting these endothelial
pathways might also benefit patients who
are unable to perform exercise due to
overwhelming pain.

References
Colleran PN, Li Z, Yang HT, Laughlin MH &
Terjung RL (2010). J Physiol 588, 1293
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Gardner AW & Poehlman ET (1995). JAMA
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Prior BM, Yang HT & Terjung RL (2004). J
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Physiol 97, 11191128.
Spier SA, Delp MD, Meininger CJ, Donato
AJ, Ramsey MW & Muller-Delp JM
(2004). J Physiol 556, 947958.
Stewart KJ, Hiatt WR, Regensteiner JG & Hirsch
AT (2002). N Engl J Med 347, 19411951.
Watson L, Ellis B & Leng GC (2008).
Cochrane
Database Syst Rev, CD000990.
Yang HT, Deschenes MR, Ogilvie RW &
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RL (1996). Circ Res 79, 6269.
Yang HT, Prior BM, Lloyd PG, Taylor JC, Li Z,
Laughlin MH & Terjung RL (2008). J
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2010 The Author. Journal compilation

2010 The Physiological Society

DOI: 10.1113/jphysiol.2010.190272

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